4′-Ethynyl-2′,3′-didehydro-3′-deoxythymidine (hereinafter referred to as 4′-ethynyl d4T) is a compound which is a promising ingredient of a drug for acquired immune deficiency syndrome (AIDS) (see, for example, Patent Documents 1 and 2). However, conventional methods for synthesizing 4′-ethynyl d4T (see Patent Document 1 and Non-Patent Document 1) require a large number of synthesis steps, making these methods high-cost and unsuitable for mass production, which is problematic.
Meanwhile, another method for producing 4′-ethynyl d4T is disclosed. The disclosed method employs furfuryl alcohol or levo-glucocenone as a starting material and requires a relatively small number of steps (see, for example, Patent Document 2). However, the problem involved in the production method; i.e., high production cost, cannot be completely solved, for the following reasons.
1) Patent Document 2 discloses kinetic optical resolution of acetyloxypyranone by use of a hydrolase. In this process, only one enantiomer of an acetyloxypyranone racemate is selectively removed via hydrolysis. Therefore, the maximum yield is limited to 50%. Meanwhile, synthesis of an optically active acetyloxypyranone from a hydroxypyranone as a raw material is also disclosed. In this synthesis, an optically active acetyloxypyranone is synthesized through dynamic kinetic optical resolution, while racemization proceeds in the reaction system (see, for example, Non-Patent Document 2). In this case, the production yield can reach 100%. However, the reaction for producing a desired enantiomer which reaction employs a lipase (Candida cylindracea or Candida rugosa) proceeds at a very low rate of reaction. In addition, there is a phrase “poor reproducibility due to an unknown reason” in Non-Patent Document 2. Thus, the production method is not considered a method suitable for mass production.
2) Patent Document 2 discloses a method for synthesizing an alkyne compound including causing an acetylene organic metal compound to act on an acetyloxypyranone. In this method, not only an alkyne compound having an acetylene moiety at the trans position to the acetyl group, but also a large amount of a diastereomer thereof having an acetylene moiety at the cis position are yielded. The diastereomer provides an enantiomer of 4′-ethynyl d4T instead of the target 4′-ethynyl d4T. Notably, Patent Document 2 does not disclose the ratio of formed alkyne compound to formed diastereomer.
3) Patent Document 2 discloses a method for synthesizing a dihydrofuran compound including causing a hydrolase to act on an alkyne compound. Although the disclosed step attains a crude product yield of about 90%, the net yield is lower, since the crude product contains reaction by-products, a diastereomer, and reaction residues.
Therefore, there is still keen demand for a low-cost method for mass-producing 4′-ethynyl d4T and a dihydrofuran compound, which is an intermediate thereof.